Targeting innate immunity in Type 1 diabetes Abstract Type 1 diabetes (T1D) is an autoimmune disease characterized by specific destruction of pancreatic insulin-producing beta cells, accompanied by beta-cell-directed autoimmunity involving autoreactive T cells and islet autoantibodies. While blood glucose levels can be controlled with diet and medication, a cure for the disease remains elusive, and T1D cannot be prevented or reversed in humans. While T1D is easy to prevent in the nonobese diabetic (NOD) spontaneous mouse model, reversing T1D in mice is more difficult. Much research has focused on autoreactive T-cells, with the goal of developing antigen-specific immunotherapy. While some of these approaches have succeeded in the NOD mouse, dozens of human clinical trials have failed. Over the past 50 years, the incidence of T1D has increased dramatically. The ?hygiene hypothesis? suggests that decreased exposure of the innate immune system to environmental immune stimulants (e.g., bacterial products such as Toll-like receptor (TLR) 4-stimulating lipopolysaccharide) affects the adaptive immune system and increases subsequent autoimmunity. During our investigations into the role of innate immunity in T1D, we have identified TLR4 antibodies that do not directly stimulate T cells but induce tolerogenic antigen-presenting cells that mediate decreased adaptive T-cell responses. We have found that treatment of acute-onset T1D in NOD mice with these anti-TLR4/MD-2 agonistic antibodies results in a remarkably high rate of disease reversal and demonstrates proof-of-concept for a novel therapeutic approach in T1D. During this Phase I project, we will identify a human counterpart to the murine antibody. We will confirm its activity in vitro in a humanized NSG mouse model. These studies will provide the basis for translation of this discovery from the murine models to humans to create the first disease-modifying treatment for T1D.